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EPO Once Weekly Improves Anemia & Quality of Life in Coinfected Patients Treated with Interferon/Ribavirin
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Reported by Jules Levin
The objective of this study was to determine the effectiveness of a weekly dosing regimen of epoetin alfa compared with standard of care (RBV dose reduction and/or discontinuation, with transfusions as needed; SOC) in alleviating anemia, improving health-related quality of life, and minimizingRBV dose reductions in HIV/HCV coinfected patients receiving combinationIFN/RBV therapy.
Anemia is associated with decreased health-related quality of life in both monoinfected patient populations, and can result in dose reduction or discontinuation of RBV in HCV-infected patients. Prospective, randomized trials have demonstrated that anemia in HIV and HCV monoinfected patients can be treated effectively with epoetin alfa therapy.
BRIEF SUMMARY: EPO was effective in correcting anemia in HIV/HCV coinfected patients receiving IFN/RBV therapy. Hemoglobin can often decline significantly within weeks after starting HCV IFN/RBV therapy. HIV-infected patients may have a predisposition for anemia due to HIV or AZT use. In this study, hemoglobin increased significantly in patients receiving epoetin alfa compared with patients receiving. The hemoglobin increases were similar inepoetin alfa-treated patients receiving or not receiving AZT and, in AZT patients, were significantly higher than in patients receiving Standard of care (SOC). All 52 patients in the had an average hemoglobin of 14.1 g/dL to 14.5 g/dL at the start of IFN/RBV therapy. 32% (n=11) of EPO patients and 62% (n=20) SOC patients dropped out within 16 weeks due to IFN/RBV discontinuation (8, EPO; 6, SOC), patient request (3, EPO; 8 SOC), physician decision (1, SOC), death (1, SOC), and lost to followup (4, SOC). The usual reason for stopping therapy is difficulty in tolerating IFN/RBV and after 12 weeks non viral response. Hemoglobon (Hb) declined to 11 before initiating EPO therapy. After 16 weeks on EPO average Hb was 13.7 vs 11.7 for patients using standard of care (reducing RBV dose and/or RBV discontinuation.
Quality of life test showed that patients receiving EPO in this study compared to patients receiving standard of care for anemia showed EPO improved their quality of life on IFN/RBV therapy more than the standard of care (RBV dose reduction and/or discontinuation). Improvements in health-related quality-of-life scores were higher in patients receiving epoetin alfa, including the mean increases in SF-12 Physical and Mental Component Summary Scale scores and , but the small sample size precluded definitive conclusions. Study investigators reported that epoetin alfa was well tolerated.
This study followed patients for 16 weeks after starting IFN/RBV so it does not evaluate the effects on sustained viral response. Studies conducted in HCV monoinfected patients also were time limited and although demonstrating improvements in fatigue, RBV dose, and quality of life, the studies did not evaluate the effect on sustained viral response. However, it ought to be expected that sustained viral responses would improve. Results from the HALT-C study show that sustaining higher RBV doses in the first few months of IFN/RBV therapy result in higher rates of sustained viral responses.
THE STUDY
Anemia is a common hematologic disorder in HIV-infected patients (pts). Combination IFN/RBV therapy for chronic HCV infection is also known to induce anemia; therefore, coinfected pts may be at higher risk for developing anemia.
Prospective, randomized trials have demonstrated that anemia in HIV andHCV monoinfected pts can be treated effectively with epoetin alfa therapy. Studies in HCV monoinfected patients have shown EPO can improve IFN/RBV related anemia & reduced hemoglobin, quality of life, and capacity to higher levels of RBV doses. Studies have shown that the level of ribavirin dose is crucial to achieving a sustained viral response to peginterferon plus ribavirin. Results from the HALT-C Study showed that maintaining maximal rinbavirin dosing during the first few months of HCV therapy is important to achieving sustained viral response. So, ribavirin dosing appears important in the first few months after starting HCV therapy. as well, previous studies have shown that ribavirin plays an important role in preventing relapse after stopping HCV therapy.
This prospective, randomized study evaluated the effect of epoetin alfa in anemic HIV/HCV coinfected pts. Previous studies have been conducted in HCV monoinfected and shown benefit.
This was an open-label, randomized, parallel-group study was conducted in 66 anemic HIV/HCV coinfected pts receiving IFN/RBV. Patients who had hemoglobin <=12 g/dL or who experienced a hemoglobin (Hb) decrease of at least 2 g/dL from the start of IFN/RBV therapy were randomized to receive either epoetin alfa 40,000 IU subcutaneously once weekly or no epoetin alfa (standard of care for anemia management; SOC) for 16 weeks. The primary endpoint of this study was to compare the hemoglobin response between epoetin alfa and Standard of Care (SOC) groups at Week 16.
66 pts were randomized (34, epoetin alfa; 32, SOC); 52 pts were included in ITT population (30, epoetin alfa; 22, SOC). Baseline (BL) characteristics were similar between the 2 treatment groups.
--Mean change in Hb (± SE) from BL to Week 16 was 2.6 ± 0.3 g/dL in the epoetin alfa group vs. 0.2 ± 0.3 g/dL in the SOC group (P<.001).
--AZT pts receiving epoetin alfa had a similar Hb response compared with non-AZT pts receiving epoetin alfa.
--Hb increases were significantly higher in patients receiving epoetin alfa vs. patientss receiving SOC in AZT patients (P=.001).
--Mean increases in SF-12 Physical and Mental Component Summary Scale scores (± SE) from BL to Week 16 were higher in the epoetin alfa group than in the SOC group;
--mean Physical Component Summary Scale score increased significantly from BL to Week 16 (6.0 ± 1.8 points; P=.004) in the epoetin alfa group.
TOLERABILITY
The study investigators reported that epoetin alfa was well tolerated; most AEs were mild to moderate in severity. The following 9 AEs were considered possibly or probably related to study drug: influenza-like symptoms, leg pain, hypertension, hypoaesthesia, diarrhea, anorexia, anemia, coughing, rash. 4 serious AEs were reported: constipation (1, epoetin alfa), substernal chest pain (1, SOC), heart disorder (1, SOC), and psychosis (1, SOC); the only serious AE in the epoetin alfa patient was considered by the investigator to be unrelated to study drug.
Study Design
An open-label, randomized, parallel-group, multicenter study in anemic HIV/HCV coinfected patients receiving IFN/RBV
Patients were randomized to receive either epoetin alfa 40,000 IU subcutaneously once weekly or no epoetin alfa (SOC) for 16 weeks
-- Epoetin alfa dosage was increased to 60,000 units once weekly after 4 weeks of therapy if Hb level did not return to patient's Hb level prior to initiating IFN/RBV
-- Epoetin alfa was discontinued after an additional 4 weeks at 60,000 units weekly if Hb level had not increased >=1.0 g/dL from the nadir Hb value, and the patient was withdrawn from the study
Patients randomized to the SOC arm were treated according to the respectiveinstitution's SOC policy (but not including epoetin alfa treatment)
Key Inclusion Criteria
Men or women 18 to 75 years of age coinfected with HIV (confirmed by branched DNA or PCR) and HCV (confirmed by detectable HCV viremia by PCR or branched DNA)
Current treatment with combination IFN/RBV for an anticipated period of 16additional weeks
Hb of <=12 g/dL or a >=2-g/dL drop in Hb compared with Hb prior to the start ofIFN/RBV therapy
Key Exclusion Criteria
Presence or history of uncontrolled hypertension (ie, diastolic blood pressure>100 mm Hg) or uncontrolled seizure disorder
Anemia attributable to factors such as iron or folate deficiency, hemolysis, orgastrointestinal bleeding
Current, active substance abuse
Serum ferritin level <50 ng/mL
Efficacy Endpoints
The primary endpoint was the mean Hb change between epoetin alfa and SOCgroups from baseline (BL) to Week 16
Secondary endpoints included RBV dosage, mean change in health-relatedquality-of-life scores (measured by Short Form-12 [SF-12] Health Survey—Acute), and transfusion utilization between epoetin alfa and SOC groups from BL to Week 16
Safety Assessments
Vital signs and adverse events (AEs) were monitored throughout the study and at each study visit
Statistical Analysis
Descriptive statistics were used for continuous variables (ie, sample size, mean, standard deviation [SD] or standard error of the mean [SE], median, and range)
Categorical variables were summarized using frequency statistics (ie, frequencyand percentage)
All analyses were on an intent-to-treat (ITT) basis (ITT population was defined as all randomized patients who received at least 1 dose of epoetin alfa or who had at least 1 follow-up Hb assessment; 52 patients were included in the ITT population)
Hb and health-related quality-of-life data were analyzed using the last-value-carried forward method
RBV dosage change data were assessed by on-treatment analysis
RESULTS
Patient Demographics and Disposition
66 patients were randomized (34 to epoetin alfa and 32 to SOC)
-- 52 patients were included in the ITT population (30, epoetin alfa; 22, SOC)
14 patients were excluded from the ITT population because they did not receive at least 1 dose of epoetin alfa or they did not have at least 1 follow-up Hb assessment (4, epoetin alfa; 10, SOC)
BL characteristics were similar between the 2 treatment groups (Table 1)
32% (n=11) epoetin alfa patients and 62% (n=20) SOC patients dropped out within 16 weeks due to: IFN/RBV discontinuation (8, epoetin alfa; 6, SOC), pt request (3, epoetin alfa; 8, SOC), physician decision (1, SOC), death (1, SOC), lost to follow-up (4, SOC).
CD4s were 390 before starting therapy. 75% of patients were on HAART. 34-44% of patients were receiving AZT. At baseline patients were receiving a median of 981 mg/day of RBV in the EPO group and 975 mg/day in the SOC group.
Hematologic Response
Mean change in Hb (± SE) from BL to Week 16 was 2.6 ± 0.3 g/dL in the epoetin alfa group vs. 0.2 ± 0.3 g/dL in the SOC group (P<.001)
AZT patients receiving epoetin alfa had a similar Hb response compared with non-AZT patients receiving epoetin alfa
-- Mean change in Hb (± SE) from BL to Week 16 was 3.2 ± 0.4 g/dL in AZT patients vs. 2.1 ± 0.4 g/dL in non-AZT patients (P =.090)
-- In AZT patients, Hb increases were significantly higher in patients receiving epoetin alfa compared with patients receiving SOC (P =.001)
Because no patients were transfused during the study, this endpoint could not be evaluated.You can see a significant increase in Figure 1 for patients receiving EPO compared to patients not receiving EPO.
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You can see in Figure 2 that patients had similar increases in Hb regardless of whether or not they were taking AZT.
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RBV Dose
Median RBV dose for the epoetin alfa and SOC groups at BL was 1000 mg/day for both groups; at Week 16, the values were 1000 mg/day and 1100 mg/day, respectively.
Health-Related Quality-of-Life Responses
Mean increases in SF-12 Physical and Mental Component Summary Scale scores(± SE) from BL to Week 16 were higher in the epoetin alfa group than in the SOC group
-- Mean increase in SF-12 Physical Component Summary Scale score from BL toWeek 16 was 6.0 ± 1.8 points in the epoetin alfa group (P =.004) vs. 2.2 ± 1.2 points in the SOC group (P =.091)
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